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Journal of medicinal chemistry
12 10, 2020;63 (23): 14700-14723.

Discovery of a Potent and Selective PI3Kδ Inhibitor ()-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.

Manojkumar R Shukla, Sukanya Patra, Mahip Verma, Gayathri Sadasivam, Nirmal Jana, Sachin J Mahangare, Prashant Vidhate, Dipak Lagad, Anand Tarage, Murthy Cheemala, Chaitanya Kulkarni, Shankar Bhagwat, Vinod D Chaudhari, Majid Sayyed, Vipul Pachpute, Ramesh Phadtare, Gopal Gole, Samiron Phukan, Brahmam Sunkara, Charudatt Samant, Manisha Shingare, Aditya Naik, Sneha Trivedi, Ajit Kumar Marisetti, Madhusudhan Reddy, Milind Gholve, Nilesh Mahajan, Sudeep Sabde, Vinod Patil, Dipak Modi, Maneesh Mehta, Prashant Nigade, Kaustubh Tamane, Swati Tota, Hemant Goyal, Harish Volam, Shashikant Pawar, Prajakta Ahirrao, Lal Dinchhana, Sadanand Mallurwar, Atul Akarte, Anand Bokare, Rupesh Kanhere, Neetinkumar Reddy, Sarita Koul, Manoj Dandekar, Minakshi Singh, Peter R Bernstein, Lakshmi Narasimham, Mandar Bhonde, Jayasagar Gundu, Rajan Goel, Sanjeev Kulkarni, Sharad Sharma, Rajender Kumar Kamboj, Venkata P Palle
Author Information
  1. Manojkumar R Shukla: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India. ORCID
  2. Sukanya Patra: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  3. Mahip Verma: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  4. Gayathri Sadasivam: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  5. Nirmal Jana: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  6. Sachin J Mahangare: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  7. Prashant Vidhate: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  8. Dipak Lagad: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  9. Anand Tarage: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  10. Murthy Cheemala: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  11. Chaitanya Kulkarni: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  12. Shankar Bhagwat: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  13. Vinod D Chaudhari: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  14. Majid Sayyed: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  15. Vipul Pachpute: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  16. Ramesh Phadtare: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  17. Gopal Gole: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  18. Samiron Phukan: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  19. Brahmam Sunkara: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  20. Charudatt Samant: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  21. Manisha Shingare: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  22. Aditya Naik: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  23. Sneha Trivedi: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  24. Ajit Kumar Marisetti: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  25. Madhusudhan Reddy: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  26. Milind Gholve: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  27. Nilesh Mahajan: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  28. Sudeep Sabde: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  29. Vinod Patil: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  30. Dipak Modi: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  31. Maneesh Mehta: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  32. Prashant Nigade: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  33. Kaustubh Tamane: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  34. Swati Tota: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  35. Hemant Goyal: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  36. Harish Volam: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  37. Shashikant Pawar: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  38. Prajakta Ahirrao: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  39. Lal Dinchhana: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  40. Sadanand Mallurwar: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  41. Atul Akarte: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  42. Anand Bokare: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  43. Rupesh Kanhere: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  44. Neetinkumar Reddy: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  45. Sarita Koul: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  46. Manoj Dandekar: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  47. Minakshi Singh: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  48. Peter R Bernstein: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India. ORCID
  49. Lakshmi Narasimham: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  50. Mandar Bhonde: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  51. Jayasagar Gundu: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  52. Rajan Goel: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  53. Sanjeev Kulkarni: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  54. Sharad Sharma: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  55. Rajender Kumar Kamboj: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
  56. Venkata P Palle: Novel Drug Discovery and Development, Lupin Ltd., Lupin Research Park, Survey No. 46 A/47A, Village Nande, Taluka Mulshi, Pune 412115, India.
PMID: 33297683 DOI: 10.1021/acs.jmedchem.0c01264

Abstract

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone , through a 1,2-disubstituted quinolizinone to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone . Compound has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

MeSH Term

Animals
Antineoplastic Agents
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Dogs
Drug Discovery
Female
Hematologic Neoplasms
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, SCID
Molecular Docking Simulation
Molecular Structure
Phosphoinositide-3 Kinase Inhibitors
Quinolizines
RAW 264.7 Cells
Rats, Sprague-Dawley
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Chemicals

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Quinolizines
Class I Phosphatidylinositol 3-Kinases
Pik3cd protein, mouse
Journal Article

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